Opinion statement
Chimeric antigen receptor (CAR) cell therapy offers patients with hematological malignancies a new therapeutic option. Traditionally, autologous T cells are used to generate CAR designed T cells for each patient. However, this method has several drawbacks, the development of allogeneic CAR cell therapy would be a promising breakthrough that could address several of these limitations. From the clinical trials that have published data, the efficacy of allogeneic CAR cell therapy did not meet the expectations. Because of the host-versus-graft (HvG) effect, allogeneic CAR cells are eliminated by the host, resulting in short-term persistence of allogeneic CAR cells and poor efficacy. It is critical to solve the HvG effect of allogeneic CAR cells. The current commonly used methods are suppressing the host’s immune system, using HLA-matched homozygous donors, reducing the expression of HLA, targeting alloreactive lymphocytes and eliminating anti-CAR activities. In this review, we will focus on the HvG effect of the “off-the-shelf” allogeneic CAR cell therapy, especially its mechanism and current methods to solve this problem and summarize relevant clinical trial data.
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Abbreviations
- CAR:
-
Chimeric antigen receptor
- HvG:
-
Host-versus-graft
- CR:
-
Complete remission
- GVHD:
-
Graft-versus-host disease
- allo-HSCT:
-
Allogeneic hematopoietic stem cell transplantation
- B-ALL:
-
B cell acute lymphoblastic leukemia
- DLI:
-
Donor lymphocyte infusion
- UCB:
-
Umbilical cord blood
- iPSC:
-
Induced pluripotent stem cell
- DLT:
-
Dose-limiting toxicity
- CRS:
-
Cytokine release syndrome
- ICANS:
-
Immune effector cell-associated neurotoxicity syndrome\
- PR:
-
Partial remission
- ADCC:
-
Antibody-dependent cell-mediated cytotoxicity
- APC:
-
Antigen-presenting cell
- VST:
-
Virus-specific T cell
- iNKT:
-
Invariant NKT
- MAC:
-
Mesenchymal stem cell
- MMP:
-
Matrix metalloproteinase
- ECM:
-
Extracellular matrix
- PTCL:
-
Peripheral T cell lymphoma
- TRAC:
-
T cell receptor alpha constant
- TRBC:
-
T cell receptor beta constant
- PEBL:
-
Protein expression blocker
- shRNA:
-
Short hairpin RNA
- DSA:
-
Donor-specific anti-HLA antibody
- HAMA:
-
Anti-mouse antibody
- scFv:
-
Single-chain variable fragment
- PNA:
-
Purine nucleotide analogue
- ALCL:
-
Activation-induced C-type lectin
- HCMV:
-
Human cytomegalovirus
- ADR:
-
Alloimmune defense receptor
- CHAR:
-
Chimeric HLA accessory receptor
- RRMM:
-
Recurrent/refractory multiple myeloma
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
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Acknowledgements
We thank all colleagues at Tianjin First Central Hospital and First Center Clinic College of Tianjin Medical University for related discussions.
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This work was supported by grants from the General Project of the National Natural Science Foundation of China (81970180 to MZ), the Science and Technology Project of Tianjin Municipal Health Committee (TJWJ2022QN030 to MZ), Key projects of Tianjin Applied Basic Research and Multi-Investment Fund (21JCZDJC01240), Science and Technology Project of Tianjin Municipal Health Committee (TJWJ2022XK018 to MZ), and the Key Science and Technology Support Project of Tianjin Science and Technology Bureau (20YFZCSY00800 to MZ), as well as Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-056B).
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YXA was a major contributor in writing the manuscript. XJ designed the outline of this manuscript. HKZ, MZ, SM have substantively revised it. MFZ, WYL reviewed and amended the draft. All authors read and approved the final manuscript.
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An, Y., Jin, X., Zhang, H. et al. “Off-the-Shelf” Allogeneic CAR Cell Therapy—Neglected HvG Effect. Curr. Treat. Options in Oncol. 24, 409–441 (2023). https://doi.org/10.1007/s11864-023-01061-8
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DOI: https://doi.org/10.1007/s11864-023-01061-8